British Journal of Anaesthesia 108 (S1): i29–i42 (2012)

doi:10.1093/bja/aer384

Organ transplantation: historical perspective and

current practice
C. J. E. Watson1* and J. H. Dark2
1
University Department of Surgery, NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
2
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
* Corresponding author: Department of Surgery, University of Cambridge, Box 202, Addenbrooke’s Hospital, Cambridge CB2 0DG, UK.
E-mail: [email protected]

Summary. Over the course of the last century, organ transplantation has overcome
Editor’s key points major technical limitations to become the success it is today. The breakthroughs

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† There has always been a include developing techniques for vascular anastomoses, managing the immune
shortfall in numbers of response (initially by avoiding it with the use of identical twins and subsequently
suitable donor organs controlling it with chemical immunosuppressants), and devising preservation solutions
available for transplant. that enable prolonged periods of ex vivo storage while preserving function. One
† Advances in challenge that has remained from the outset is to overcome the shortage of suitable
immunosuppression have donor organs. The results of organ transplantation continue to improve, both as a
reduced the incidence of
consequence of the above innovations and the improvements in peri- and
acute rejection but have not
affected chronic immune
postoperative management. This review describes some of the achievements and
damage. challenges of organ transplantation.
† Current research is directed
at techniques to improve
Keywords: immunosuppressants; organ preservation; organ preservation solutions;
organ preservation.
organ transplantation; tissue and organ procurement

A brief history of transplantation excessive ischaemic injury and kidneys from live donors
began to be used. Some of these were from the relatives of
Kidney transplantation the recipient; others were unrelated patients having a good
Since Jaboulay and Carrel developed the techniques kidney removed for other reasons. The surgical technique
required to perform vascular anastomoses at the turn of also needed refinement; while a kidney based on the thigh
the last century, there has been a desire to treat organ or arm vessels might be technically straightforward, and pos-
failure by transplantation. Jaboulay was the first to sibly adequate for the short-term treatment of acute renal
attempt this in 1906, treating two patients with renal failure, it was not a realistic solution for the long term.
failure by transplanting a goat kidney into one and a pig That solution came from France in 1951 and involved
kidney into the other; in both cases, he joined the renal placing the kidney extraperitoneally in an iliac fossa, where
vessels to the brachial vessels.1 Both transplants failed the external iliac vessels are easy to access and the
and both patients died. At that time, there was no alterna- bladder is close by for anastomosis to the donor ureter;
tive to death if renal failure developed, and it would be this is the technique still used today.
another 38 yr before the first haemodialysis machine was Having overcome the technical issues of vascular anasto-
invented. The first use of a human kidney for transplant- mosis and placement of the kidney, there remained the
ation followed in 1936 when Yu Yu Voronoy, a Ukrainian problem of the immune response. Medawar’s work during
surgeon working in Kiev, performed the first in a series of and after the Second World War studying the rejection of
six transplants to treat patients dying from acute renal skin grafts had demonstrated the potency of the immune
failure secondary to mercury poisoning, ingested by its system.2 At that time, attempts to control the immune
victims in an attempt to commit suicide. All the transplants system using irradiation had proved either ineffectual or
failed, in large part because of a failure to appreciate the lethal. The first successful transplant therefore came about
deleterious effect of warm ischaemia; the first kidney was by avoiding an immune response altogether, which Joseph
retrieved 6 h after the donor died. Murray’s team achieved by performing a kidney transplant
One limitation to transplantation then, as now, was the between identical twins.3 There then followed a series of
lack of suitable donor organs. The initial pioneers had used identical twin transplants around the world, with the first in
animal organs or organs from long deceased humans. In the UK being performed in Edinburgh by Woodruff and
the 1950s, there came a realization of the need to avoid colleagues4 in 1960.

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [email protected]
BJA Watson and Dark

Liver transplantation excellent.12 Progress over the next 15 yr was dogged by

Success in clinical liver transplantation took longer to realize airway healing complications and the longest survivor, that
than kidney transplantation. The recipient is usually much of Derom in Belgium, lived only 6 months. Reitz and collea-
sicker than a renal transplant recipient, and the operation gues13 performed the first successful heart –lung transplant
is a more formidable undertaking and is usually performed in 1981 and the Toronto group achieved successful single-
in the presence of a significant coagulopathy. Initial lung transplantation a few years later. The bilateral lung
attempts at liver transplantation in 1963 by Starzl5 in transplant, with separate hilar anastomoses, was introduced
Denver were unsuccessful, but following a move to Pittsburgh in 199214 and is now the standard procedure for the majority
in 1967, his results improved. The first transplant in Europe of patients.
was performed by Calne in Cambridge the following year.6
Starzl had preceded his clinical attempts with extensive Immunosuppression
animal work during which he identified the need to cool
Historical background
the liver before transplantation and to maintain venous
return to the heart using veno-veno bypass to shunt blood In the 1950s, success in bone marrow transplantation

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from the inferior vena cava (IVC) and portal circulation to between siblings had been achieved using total body irradi-
the superior vena cava. In spite of these innovations, it ation,15 and for a while, this was pursued in kidney trans-
would be another two decades, following improvements in plantation but with little success, although two recipients
patient selection, perioperative management, and post- of kidneys from a non-identical twin did achieve some long-
operative immunosuppression, before liver transplantation term function.16 17 The real breakthrough came with the
could be considered a successful treatment for patients in introduction of chemical immunosuppression that could sup-
liver failure. press the immune system sufficient to permit engraftment of
the transplant, while at the same time being suitably specific
such that other protective immune responses remained
Heart transplantation intact. The first successful agent was azathioprine, a purine
The pioneer in cardiac transplantation was the American analogue and less toxic derivative of 6-mercaptopurine
surgeon Norman Shumway working in Palo Alto. A series of which had itself been shown to be effective in permitting
animal experiments had enabled him to work out the opera- long survival of dog kidney transplants.18 Azathioprine is
tive strategy, which involved cooling the heart and leaving thought to act by inhibiting DNA replication and thus block-
part of the atria in situ to reduce the number of anastomoses ing proliferation of lymphocytes. Coupled with prednisolone,
required.7 However, it was Christiaan Barnard, working in azathioprine enabled transplantation of unrelated donor
Cape Town and having visited Shumway’s unit, who per- kidneys with around 50% still functioning at 1 yr, a significant
formed the first human heart transplant in 1967.8 The follow- achievement in an era when dialysis was still in its infancy
ing year, on the same day that Calne performed the first liver and renal failure was usually a death sentence.
transplantation in the UK, Ross9 performed the first heart
transplant, at the National Heart Hospital in London. During Modern immunosuppression
the 12 months after Barnard’s transplant, more than 100
cardiac transplants were performed at centres around the Ciclosporin
world. Results were very poor, with few patients surviving The modern immunosuppressive era came with the discovery
to leave hospital. Over the next decade, only Shumway’s of the immunosuppressant effects of ciclosporin in the
group and that of Cabrol in Paris remained active. A key mid-1970s. Initially developed as an antifungal drug, ciclo-
advance was the introduction of endomyocardial biopsy by sporin was found to be toxic in rodents, although curiously,
Caves in 1973 and the classification of histological rejection it was noted to permit skin grafts between them.19 Two
by Billingham.10 Only with the introduction of ciclosporin in years later, the drug had undergone its first clinical trials in
the early 1980s did cardiac transplantation become wide- Cambridge and been shown to be a potent immunosuppres-
spread. By 1986, more than 2000 procedures annually were sant.20 Ciclosporin improved dramatically the results of
being reported to the Registry of the International Society kidney transplantation such that today 90–95% of kidney
for Heart and Lung Transplantation (ISHLT). A decade later, transplants on ciclosporin survive 1 yr; it also provided
this had more than doubled, although there has subsequent- sufficient immunosuppression to permit successful liver,
ly been a decline from that peak in all parts of the world.11 pancreas, heart, and lung transplantation.
UK numbers similarly were at their highest in the Ciclosporin inhibits T cell proliferation by blocking activa-
mid-1990s, with more than 300 transplants shared tion. When foreign peptide antigen is presented to the recipi-
between seven centres, but have now decreased to less ent’s T cell, binding to the antigen-binding groove of the
than half that number. major histocompatibility complex (MHC) triggers activation
The first lung transplant was performed by Hardy, in 1964. of the T cell. The rate-limiting step in the activation
Although the patient died of renal failure after 3 weeks, the cascade is a serine –threonine phosphatase called calci-
case is notable because the lung was donated after circula- neurin. When ciclosporin enters a lymphocyte, it binds to
tory death (DCD) and early function of the lung was an immunophilin called cyclophilin. This ciclosporin –

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Organ transplantation BJA
cyclophilin complex inhibits calcineurin and so arrests T cell reduce immune-mediated vasculopathy.22 In addition,
activation. Its principal side-effects are neurotoxicity, mTOR inhibitors appear to have some anti-tumour proper-
nephrotoxicity, and diabetogenesis, although it also has ties, so have been used in patients transplanted for tumour
other metabolic effects. In spite of careful monitoring of (such as primary hepatocellular carcinoma) or who develop
ciclosporin blood levels, up to 5% of patients who take ciclo- malignant tumours post-transplant, such as Kaposi’s
sporin will become diabetic, and a significant proportion will sarcoma.23 Indeed, temsirolimus, another analogue of siroli-
develop renal impairment. Calcineurin inhibitor (CNI) nephro- mus, has been developed as an anti-neoplastic agent and is
toxicity also causes renal failure in the native kidneys of licensed for use in advanced renal carcinoma.24
many recipients of non-renal transplants, its incidence
being highest in those receiving cardiothoracic organs.
Mycophenolic acid
Mycophenolic acid (MPA) is the active component of myco-
Tacrolimus
phenolate mofetil and mycophenolate sodium. MPA blocks
Like ciclosporin, tacrolimus is a fermentation product of a inosine monophosphate dehydrogenase, an enzyme required
bacterium, and also acts by inhibiting calcineurin. However,

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for the de novo synthesis of guanosine nucleotides. While
tacrolimus binds a different immunophilin, the 12 kDa other cells have salvage pathways by which guanosine
FK506 binding protein (FKBP12). The tacrolimus–FKBP12 nucleotides may be synthesized, lymphocytes do not. MPA
complex binds to a different site on calcineurin to achieve thus blocks lymphocyte proliferation by blocking DNA synthe-
the same effect as ciclosporin. It is more powerful than sis. It is more potent than azathioprine and is associated
ciclosporin, and has proved superior in most forms of organ with a greater reduction in acute rejection; however, it is
transplantation; it has also permitted intestinal transplant- not as potent as mTOR or CNIs, and is generally used in com-
ation to be successfully undertaken. It shares the same prin- bination with one of those drug classes. Its main toxicity is in
ciple toxicities as ciclosporin, although the incidence of the gastrointestinal tract, with diarrhoea often being dose
diabetes and neurotoxicity are higher. The two CNI drugs limiting.
have different cosmetic effects, with ciclosporin causing
hypertrichosis and gingival hypertrophy while tacrolimus
can cause alopecia. Induction therapy
Immunosuppression is required for as long as the graft func-
Sirolimus and everolimus: inhibitors of the mammalian tions; if it is stopped, then rejection occurs and the graft is
target of rapamycin lost. However, the intensity of immunosuppression is not con-
Sirolimus, formerly known as rapamycin, is one of a class of stant. High levels of immunosuppression are required soon
drugs that inhibit the mammalian target of rapamycin after transplant, but thereafter doses can be reduced to a
(mTOR). Sirolimus was discovered as a fermentation lower maintenance level. Immunosuppression in that initial
product of a micro-organism originally isolated in soil period after transplantation is often enhanced by the use of
samples from Easter Island (known locally as Rapa Nui); ever- a biological agent, such as a monoclonal or polyclonal anti-
olimus is a chemical modification of sirolimus which has body, many of which may be started intraoperatively or given
improved its oral bioavailability and reduced its half-life immediately before surgery. Historically, anti-lymphocyte
from around 60 h to nearer 24 h. globulin, produced by inoculating horses or rabbits with
mTOR is a serine/threonine protein kinase that is involved human thymocytes and lymphocytes, was used, but this has
in the regulation of cell growth and proliferation and acts as been largely supervened by monoclonal antibodies that
a central mediator of protein synthesis and ribosome biogen- target specific lymphocyte subsets. One such example is basi-
esis. Blockade of mTOR inhibits the cellular proliferation liximab, a chimeric monoclonal antibody to the CD25 antigen
response to a variety of signals, including cytokines such as on the alpha chain of the interleukin 2 receptor, which is only
interleukin 2. These effects are not limited to lymphoid expressed on activated T cells. Basiliximab therefore targets
tissue, so that blockade can also interfere with wound only activated T cells, and in the context of transplantation,
healing by impairing the normal fibroblast response to fibro- these are the ones involved in allorecognition and initiation
blast growth factor. Sirolimus and everolimus achieve their of an immune response. It has been shown to significantly
effects by first binding the FKBP12 immunophilin, and it is reduce the incidence of graft rejection, although it is unclear
this complex that inhibits the mTOR pathway. whether it affects long-term survival. Alemtuzumab is
mTOR inhibitors are less nephrotoxic than CNIs, although another monoclonal antibody that is increasingly being
they do have glomerular effects and can cause massive pro- used, and acts by depleting circulating T and B cells. Like the
teinuria; they can also cause diabetes but not as commonly polyclonal anti-lymphocyte globulins, the first dose of alemtu-
as the CNI inhibitors. More importantly, the mTOR inhibitors zumab is associated with massive cell lysis and release of cyto-
can cause a life-threatening pneumonitis,21 which resolves kines that can cause dramatic haemodynamic instability, an
on treatment withdrawal. They are generally used as alterna- important consideration if administration occurs in the peri-
tives to CNIs in patients with impaired renal function, but in operative period. This can be reduced by prior administration
heart transplantation, mTOR inhibitors have been shown to of steroids and an antihistamine.

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BJA Watson and Dark

Immunosuppressive regimens access to the waiting lists. At the end of March 2010, there
Immunosuppression is normally given as a combination of were almost 8000 patients on the national waiting lists for
agents with different sites of action and different side-effect an organ transplant in the UK, with more than 7000 waiting
profiles, following similar principles to antimicrobial and anti- for a kidney or combined kidney and pancreas, 360 a liver,
neoplastic chemotherapy. The most common regimen used 254 a lung, and 144 a heart or heart and lungs.30 Patients
today in kidney transplantation is a CD25 monoclonal anti- are generally considered for listing for a transplant if they
body such as basiliximab, followed by a combination of tacro- have a better than 50% chance of surviving 5 yr after trans-
limus, mycophenolate, and steroids.25 The regimen will vary plant, although the actual recipient survival after transplant-
according to the perceived immunosuppressive challenge ation of all organ-types transplants is far better than this
that the transplant poses, with more powerful immunosup- (Figs 2–6). Greater availability of suitable donor organs
pression being used where the risk of rejection is perceived would allow these arbitrary thresholds to be relaxed.
to be highest. Similarly different organs and different
diseases require different protocols.

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Death while awaiting a transplant
Complications of immunosuppression
A significant number of patients fortunate enough to be on
In addition to individual drug side-effects, patients who are
the transplant waiting list will die or be removed from the
immunosuppressed have a higher risk of infection and malig-
list at a later date, usually because they become too unfit
nancy. Commonly encountered infections include pneumo-
for transplantation (Table 1). Hence while 62% of patients
cystis jiroveci and cytomegalovirus, although other unusual
awaiting a heart will be transplanted within a year, 12%
pathogens such as aspergillus are also more common in
will die and a further 7% will be removed from the waiting
transplant recipients. Patients are usually given anti-
list in the same year. The situation is worse for lungs where
microbial prophylaxis for the first 3–6 months, after which
27% of patients will either die or be removed from the
the effects of the induction immunosuppression have worn
waiting list in the first year of listing, while only 31% will be
off and the baseline immunosuppression has been reduced.
transplanted; only a half of those patients listed for a lung
While the incidence of all malignancies is higher in
transplant will ever be transplanted.
immunosuppressed patients, those with a possible viral aeti-
ology are very high. Hence, post-transplant lymphoma due to
EB virus affects around 2% of recipients, and non-melanoma
skin cancer is particularly high, with human papilloma virus Extending the envelope: live donors and less than
implicated.26 ideal donors
Future possibilities in immunosuppression In an effort to address the widening gap between demand and
supply of donor organs, there has been an increase in the
Advances in immunosuppression have reduced the incidence
numbers of live donors, such that there are now more live
of acute rejection, but have not affected the incidence of
donors than deceased donors per year in the UK, as there
chronic immune damage in any organ, although the demon-
are in the USA.30 The numbers of deceased organ donors
stration that everolimus inhibits coronary allograft vasculo-
have increased recently, but largely through increases in DCD
pathy in heart transplant recipients may be a step towards
which has increased 10-fold in the last decade and now com-
this.22 The goal of transplantation is the induction of toler-
prises one-third of all deceased organ donors (Fig. 1).31
ance, a state of specific unresponsiveness towards the
In addition to the increases in the numbers of DCD donors,
donor. While this is readily and reliably achieved in animal
there has been an increase in the use of organs from donors
models, it is rarely achieved clinically. Some patients who
that would previously have been considered to be inappropri-
have discontinued their medication (often due to non-
ate. For example, the proportion of deceased donors who
compliance) do appear to develop tolerance. This seems to
were aged .60 yr has increased from 14% in 2000 –1 to
be most common after liver transplantation, but has been
26% in 2009 –2010, and the proportion with a BMI of ≥30
reported after other organ transplants.27 Nevertheless, such
kg m – 2 has increased from 13% to 24% over the same
a state appears to be brittle, and readily broken when the
period. There has also been a change in the common
immune system is challenged, for instance, by an intercur-
causes of donor death, with fewer donors dying after head
rent infection such as influenza. It may be more realistic to
injury and more after intracranial haemorrhage, organs
aim for a state of ‘almost tolerance’, where minimal
from the latter being associated with less good transplant
immunosuppression is required.28 29
outcomes than the former. Recipients now have some diffi-
cult choices: turn down an organ which has associated
Trends in organ donation risks in order to wait for the possibility of a better one,
Since the start of transplantation, there has been a shortfall in while risking death without a transplant, or alternatively
the number of suitable donor organs available, and as the accept a transplant from a live donor putting them at risk
numbers of patients on the waiting lists has progressively of death, a risk that may be as high as one in 200 for live
increased, so too has the number of patients who are denied donation of a liver lobe.

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Organ transplantation BJA

Table 1 Outcomes of UK patients placed on the waiting list for transplants (for the heart, lung, and pancreas, transplant data are for adult
non-urgent patients listed between April 1, 2006, and March 31, 2007; for livers, data are for adult non-urgent patients listed between April 1,
2007, and March 31, 2008; and for kidneys, data relate to adult patients listed between April 1, 2004, and March 31, 2005). Data from NHS Blood
and Transplant Activity Report 2009/2010. *For livers, the data are for 1 and 2 yr, not 1 and 3 yr

Organ Proportion of patients at 1 yr Proportion of patients at 3 yr*

Transplanted (%) Still waiting (%) Died (%) Removed (%) Transplanted (%) Still waiting (%) Died (%) Removed (%)
Heart 62 19 12 7 69 4 16 12
Lung 31 42 21 6 51 6 30 13
Liver 69 11 10 9 75 2 11 12
Kidney 25 71 2 2 47 41 7 5
Pancreas 64 30 3 3 78 12 3 7

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1200
Live donors
DBD donors 1061
DCD donors
1000 961

858

800
736
703 716 697 702
664
637 634 623
599 609 611
600

472 485
372 397
400 386
336
288
200
200 159
127
73 87
42 61
37
0
2000–1 2000–2 2000–3 2000–4 2000–5 2000–6 2000–7 2000–8 2000–9 2000–10

Fig 1 Trends in organ donors in the UK, 2000 –10. The figure shows the change in the numbers of different types of organ donor in the last
10 yr. There are now more live donors in the UK, most of whom give a single kidney, although around 20 liver lobes are donated each year. The
number of donors after circulatory death (DCD) has also increased nine-fold in the last 10 yr, while there has been little change in the number
of DBD in the last 3 yr. This itself is notable given the decreasing numbers of DBD donors until 2007 –8.

Xenotransplantation pressures and core temperatures (the latter being 398C in

The use of organs from animals has long been seen to be a the pig). There are also differences in structure and activity
solution to the shortage of donor organs. In spite of much of a variety of proteins, particularly those involved in the
effort, there is still no successful clinical xenotransplant pro- clotting and complement cascades and cell regulation.32
gramme. The pig has long been thought to be the most likely The second concern relates to zoonotic infection, particu-
species to provide donor organs, since the organs are physic- larly from porcine endogenous retroviruses (PERVs).33 Several
ally of similar size to human organs, and the species has a PERVs have been identified in the genome of pigs, some of
short gestation period, produces many offspring, can be suc- which have been shown to infect human cells in culture.
cessfully farmed, and can be genetically manipulated. Aside The significance of these in clinical transplantation in an
from ethical considerations, there are three main obstacles immunosuppressed recipient is unknown, but a cause for
to successful xenotransplant: physiological, microbiological, concern.
and immunological. The third challenge is immunological.34 Genetic manipula-
Porcine and human physiology differs in a number of im- tion of pig endothelium to express human complement
portant aspects. There are differences in organ perfusion regulatory proteins overcomes the immediate threat of

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BJA Watson and Dark

antibody-mediated hyperacute rejection response that ensuring diastolic arrest and rapid reduction of metabolic ac-
would otherwise be a consequence of humans having pre- tivity that is added to the effects of cooling. For pulmonary
formed natural antibodies to porcine antigens. However, preservation, almost all centres worldwide use a low-
the threat of subsequent cell-mediated rejection has potassium/dextran solution (commercially available as Perfa-
proven more resistant to genetic manipulation, with the cel- dex) to which a prostaglandin vasodilator has been added,
lular response to pig antigens that are indirectly presented and gentle inflation of the lungs to aid perfusate distribution.
on human MHC molecules being particularly aggressive. It Additional low-pressure retrograde perfusion via the pulmon-
would appear that xenotransplantation is still some years ary veins is of proven advantage, washing clot and debris out
away from clinical practice. of the arterial side and possibly giving additional cooling via
the bronchial circulation.
Organ preservation
In the absence of a circulation, cells rapidly switch from Cold storage
aerobic to anaerobic metabolism, which requires 19 times Different organs exhibit different tolerances to warm and
more glucose substrate to generate adenosine triphosphate cold ischaemia, in part related to the nature of the

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(ATP) than aerobic metabolism. The result is rapid consump- organ and in part because of the demands on the organ
tion of energy substrate, depletion of intracellular energy after transplantation. Hence the heart, which has to func-
stores, and accumulation of toxic metabolites and lactic tion immediately upon transplantation, has the shortest
acid. As ionic membrane pumps fail for lack of ATP, the cell tolerance to cold ischaemia, and each hour beyond the
membrane depolarizes as sodium enters and potassium first results in a measurable reduction in survival;38 it
leaves the cell. Eventually, cellular integrity is lost. The should ideally be transplanted in ,4 h. This in turn man-
purpose of organ preservation is to prevent or arrest these dates that heart retrieval cannot begin until a suitable
changes as quickly as possible. This is achieved primarily by recipient has been identified, admitted to transplant
cooling: metabolic rate is halved at temperatures below centre, and indeed prepared for surgery. Although lungs
108C, and at 48C is ,10% of that at normal body are slightly more tolerant, with good function to be
temperature. expected as long as cold ischaemia is ,6–8 h, similar
principles very often apply.
Preservation solutions for the liver, kidney, Kidneys, in contrast, need not work immediately and
and pancreas the recipient can be supported on dialysis until they do
Preservation solutions have been devised to counter the work. Nevertheless, there is an increased recognition
effects of prolonged ischaemia and minimize injury asso- that even kidneys fare better if transplanted as quickly
ciated with reperfusion. They contain a physiological as possible, and ideally within 18 h. The liver and pancreas
buffer to maintain pH in the face of accumulating lactic lie in between and are best transplanted within 12 h. For
acid (e.g. phosphate or citrate) and large molecules such DCD organs, those values go down to 12 and 6 h, respect-
as mannitol or raffinose to maintain an intravascular ively, for the kidney and liver/pancreas. Registry analysis
osmotic potential in the absence of blood, thus minimizing shows that with each type of organ, the duration of cold
cell swelling. In addition, the early fluids had an electrolyte ischaemia is one of the more significant variables in de-
composition more akin to intracellular fluid than extracellu- termining outcome after transplantation,39 – 41 and one
lar fluid, with high potassium and low sodium concentra- of the only modifiable factors. Moreover, it is a continuous
tions to minimize diffusion. Indeed, the two most variable, and any period of cold or warm ischaemia is
commonly used solutions today, Marshall’s solution undesirable.
(Soltran, a preservation solution only suitable for kidneys)
and the University of Wisconsin solution (ViaSpan, suitable DCD and warm ischaemia
for the kidneys, liver, and pancreas), are high potassium, Organ donors in whom death has been certified by neuro-
low sodium solutions.35 36 This fluid composition has impli- logical criteria (donation after brain death, DBD) are taken
cations when the organs are reperfused with blood in the to theatre supported on a ventilator with the heart still
recipient, since the preservation solution is washed from beating. After mobilization of the organs and administration
the transplanted organ into the circulation carrying with of heparin, the circulation is stopped by cross-clamping the
it its potassium load. More recent work suggests that a aortic arch, draining the vena cava, and immediately flushing
composition akin to intracellular fluid is not essential, and ice-cold preservation solution through the distal aorta thus
low potassium, high sodium solutions have been intro- keeping warm ischaemia, and accompanying anaerobic
duced (e.g. Celsior), although they are not widely used in metabolism, to a minimum.
the UK.37 The organs retrieved from DCD donors are exposed to a
more prolonged period of warm ischaemia than those
Preservation solutions for the heart and lung retrieved from DBD donors. The warm ischaemic time has
Cardiac preservation solutions tend to be adaptations of traditionally been assessed as the time interval between
cardioplegia solutions, with a high potassium content onset of irreversible asystole and subsequent cold

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Organ transplantation BJA
perfusion. This time interval includes the 5 min of continu- Normothermic regional perfusion of the abdominal
ous observation required to confirm death,42 together with organs in DCD donation
time taken to transfer the donor to the operating theatre,
Surgeons in Barcelona have pioneered a technique to
perform the initial laparotomy, cannulate the aorta and
improve the outcomes of organs retrieved from uncontrolled
IVC, and begin cold perfusion. However, it is now recog-
DCD donors. After death, a double-balloon catheter is passed
nized that organ hypoperfusion and warm ischaemia
from the femoral artery into the aorta where the balloons are
begin some considerable time ahead of asystole as cardio-
inflated to isolate the abdominal aorta. Venous outflow is via
vascular and respiratory functions slowly collapse after
the ipsilateral femoral vein. The catheters are then con-
treatment withdrawal. Thus, while the warm ischaemic
nected to an extracorporeal membrane oxygenator (ECMO)
time may be 10 – 30 min, the true ‘functional’ warm is-
circuit to perfuse the abdominal organs with circulating
chaemia may extend beyond an hour. With the exception
warm, oxygenated blood. This permits recovery from the
of the lung (which can be inflated with oxygen immediate-
warm ischaemic injury that occurs around death and early
ly after entering the operating theatre), all organs that
results suggest that it improves the outcomes of kidneys
suffer warm ischaemia tolerate subsequent cold ischaemia
and livers retrieved from such donors.44 – 46 Having replen-

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very badly.
ished ATP, the cells in the organs are then better placed to
withstand subsequent cold storage. The technique has
been adopted in France and in parts of the USA,47 and
Outcomes of organs from DCD donors compared initial studies are underway in the UK in controlled DCD
with those from DBD donors donors with promising early results. With the numbers of
DCD donors, increasing the use of normothermic regional
The extra warm ischaemic damage suffered as a conse-
perfusion may become standard practice in these donors.
quence of DCD donation manifests in different ways. For
kidneys, there is an increased incidence of acute tubular Cold machine perfusion of the kidney
necrosis that results in a delay in resumption of renal func-
After removal from the deceased donor, kidneys are usually
tion, necessitating post-transplant dialysis in more than
placed in a bag of preservation solution in a box of ice,
half of the recipients. Livers transplanted from DCD
keeping the temperature of the organ around 48C. While
donors have a higher incidence of primary non-function re-
such static cold storage has the advantage of being simple
quiring urgent retransplantation or resulting in death, and
and facilitating easy transport of the kidney from donor hos-
also more anastomotic and intrahepatic biliary strictures
pital to recipient hospital, nevertheless it has been argued
which may result in recurrent cholangitis and necessitate
that the kidney may be better preserved if it is placed on a
retransplantation; DCD livers are also associated with
machine where cold preservation solution is pumped
poorer graft and patient survival than DBD livers,43 but su-
through it, flushing out the small capillaries and the accumu-
perior survival compared with remaining on the waiting
lating metabolic products. Particular attention has focused
list. There are less data for pancreas transplantation, but
on cold machine perfusion of kidneys from DCD donors,
review of the UK Transplant Registry data suggests a
which potentially have most to gain from improved
higher incidence of graft thrombosis and pancreas loss
storage. However, two recent randomized controlled trials
with DCD donor pancreases compared with DBD donor
using the same machines have produced contrary results,
grafts. In contrast, lungs transplanted after DCD donation
so the true value of cold machine perfusion remains to be
function at least and also standard DBD lungs.44 This
determined.48 49 As yet, there are no commercially available
may be attributed to both the arrest of warm ischaemia
machines for the cold perfusion of non-renal organs.
(by prompt re-inflation of the lungs with oxygen and the
resulting restoration supply of oxygen to the pulmonary
Normothermic machine perfusion
alveoli) and the absence of many of the deleterious pul-
monary consequences of brain-stem death such as neuro- The liver
genic pulmonary oedema. Although avoidance of unnecessary warm ischaemia is es-
sential, there is no doubt that cold preservation is also dam-
aging to organs, some more so than others. Steatotic (fatty)
livers are particularly susceptible to damage by cold preser-
Improving organ preservation vation, since the intrahepatic fat globules solidify and
In the last two decades of organ transplantation, the focus damage the hepatocytes and hepatic microcirculation,50
has been on improving immunosuppression to achieve pro- accounting in part for the high incidence of non- and poor
longed graft survival. Today, the emphasis has changed function in such livers. One solution would be to preserve
and organ preservation is being revisited in an attempt to the livers at normal body temperature.51 Since metabolism
improve outcomes. This has been spurred on by the rapid in- is fully active at 378C, such preservation needs to involve
crease in DCD donation, and the use of more organs from an oxygenated perfusate. Normothermic perfusion devices
older donors. There are three strategies that are currently for the liver are currently in early trials in the UK and the
being evaluated. first clinical transplants with such livers are expected this

i35
BJA Watson and Dark

year. Preclinical evidence suggests that such a technique will dead organ donors, and in part because most studies are
offer considerable advantages over cold preservation, par- insufficiently well powered to show any significant differ-
ticularly for livers that have experienced significant periods ence. A large correctly powered study of remote ischaemic
of warm ischaemia as occurs in DCD donation.52 preconditioning in living kidney donation is currently
underway in the UK; large properly powered studies in
The heart deceased organ donation are awaited.
The ability to extend the safe preservation period for hearts
has led to much interest in normothermic perfusion. Such a Clinical results in organ transplantation
device perfuses the coronary arteries and the heart itself The results of transplantation of all solid organs have
does not need to contract; this does allow pre-transplant as- improved year on year in spite of the fact that fewer
sessment of pump function. One such device, the TransMe- ‘ideal’ donor organs are used; instead, donors are now
dics Organ Care SystemTM is currently undergoing phase older and more commonly donate after a spontaneous
2 trials in the USA (http://www.transmedics.com/wt/page/ cerebrovascular event rather than after isolated traumatic
PROCEED_II) and has been evaluated in Europe, although brain injury.

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the results are not yet published.
Kidney transplantation
The kidney
There are around 22 000 patients in the UK alive with a func-
The ability to preserve a kidney in the cold for long periods tioning kidney transplant, and a further 25 000 on dialysis, of
has removed the incentive to develop normothermic whom 7000 are active on the kidney transplant waiting list.59
preservation. However, recent work suggests that a period Figure 2A illustrates the underlying diagnosis in those
of normothermic preservation immediately before implant- patients, while Figure 2B illustrates the long-term outcomes
ation using a red cell-based plasma-free perfusate may after kidney transplantation. As can be seen for all transplant
reduce reperfusion injury;53 clinical trials of this are currently types, there is an initial rapid decrease in graft (and patient)
underway with encouraging early results. survival in the first few months post-transplant and there-
after a slow attrition; around 70% of grafts will be functioning
The lung at 10 yr. The early graft losses include technical problems
Ex vivo lung perfusion is probably the furthest advanced of such as vascular thrombosis, and also losses due to rejection.
all the normothermic organ preservation techniques. Initial Late losses are usually a result of a combination of pre-
work showed that lungs can be perfused with a blood- existing donor disease, recurrence of the recipient’s own
based perfusate and assessed ex vivo before transplant- disease (e.g. IgA nephropathy), and immunological response
ation.54 The lungs are ventilated via a tracheal tube in the to the graft.
trachea/bronchus and perfused via a cannula in the pul-
monary artery. After passing through the lungs, the perfus- Pancreas transplantation
ate passes back to an ECMO device where it is Most pancreas transplants are performed in patients with
deoxygenated by a nitrogen/carbon dioxide-rich gas diabetic nephropathy who either also require (80%) or who
mixture, warmed to 378C, and passed from there through have previously received (15%) a kidney transplant. A small
a leucocyte filter back to the lungs. The ability of the number of patients with life-threatening hypoglycaemic un-
lungs to oxygenate the perfusate gives an indication of awareness receive a pancreas alone. In this latter group of
function. There is now considerable evidence that lungs patients, their symptoms have to be sufficiently troublesome
that would otherwise have been considered not suitable to warrant a major laparotomy and the continued immuno-
for transplantation could be ‘reconditioned’ ex vivo, with suppression that is involved.
the potential for making significantly more lungs available Although the first pancreas transplantation in the UK was
for transplantation.55 – 57 in 1978, activity has only increased in the last few years,
largely as the result of national commissioning along
Ischaemic preconditioning similar lines to cardiothoracic and liver transplantation. The
Ischaemic preconditioning, either by rendering the target number of pancreas transplants has increased from around
organ ischaemic (direct ischaemic pre-conditioning) or by 40 in 2000 to nearly 200 10 yr later. The results of pancreas
rendering a different organ or tissue ischaemic (remote transplantation have improved rapidly as experience
ischaemic preconditioning), may help reduce reperfusion accrued, with the most recent results now as good as
injury after organ transplantation. Although animal work those in the USA (Fig. 3).
suggests the benefits of such an approach, there have A proportion of donated pancreases are processed to
been few large-scale trials to substantiate these observa- extract islets for isolated islet transplantation. This is
tions clinically, particularly with organs from deceased also indicated for patients with life-threatening hypogly-
donors, with the studies that have been published offering caemic unawareness, and has the advantage that it
conflicting results.58 In part, this may reflect the very ab- avoids a significant surgical intervention. However, the ex-
normal physiological state that exists after coning in brain- traction, isolation, and transplantation process is not very

i36
Organ transplantation BJA

A Unknown, 4%

Uncertain aetiology
Other, 14% GN (not biopsy proven),
20%

Renal vascular disease, 4%

Hypertension, 6%
GN (biopsy proven), 16%

Polycystic kidney disease,

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10%

Diabetes, 14% Pyelonephritis, 12%

B 100

90

80

70
% graft survival

60

50

40
Year of transplant
30 (number at risk on day 0)
1996–8 (3285)
20 1999–2001 (2864)
2002–4 (2747)
10
2005–8 (2919)
0
0 1 2 3 4 5 6 7 8 9 10
Years since transplant

Fig 2 (A) Primary renal disease in prevalent patients on renal replacement therapy in the UK on December 31, 2008 (GN, glomerulonephritis).59
(B) Long-term graft survival after first kidney only transplant in the UK from DBD donors, January 1, 1996– December 31, 2008.

efficient such that most recipients continue to require

100
insulin afterwards, although they are symptomatically
90
much improved.
80
70
% graft survival

60 Liver transplantation
50 The most common indication for liver transplantation
40
Year of transplant
today is hepatocellular carcinoma (hepatoma) occurring
30 (number at risk on day 0) in a cirrhotic liver (Fig. 4A). The hepatoma(s) must be
20 2002–4 (156) small and confined to the liver; current guidelines indicate
10 2005–8 (524)
that patients with a single tumour under 5 cm or no more
0 than 5 tumours all under 3 cm are suitable candidates
0 1 2 3
Months since transplant
with least chance of recurrence or extra-hepatic spread
of the tumour. The majority of these hepatomas occur
against a background of hepatitis C-induced cirrhosis,
Fig 3 Pancreas graft survival after first combined kidney and
pancreas transplant in the UK, January 1, 2002– December 31,
which also accounts for 14% of transplants in patients
2008. without tumours. Alcoholic liver disease is the next most
common indication for liver transplantation. Potential

i37
BJA Watson and Dark

A Metabolic liver disease,

5% Other liver
disease, Hepatocellular cancer;
Auto-immune + 7% 25%
cryptogenic disease, 7%

Primary biliary cirrhosis,

10%

Hepatitis C cirrhosis, 13%

Primary sclerosing
cholangitis, 9%

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Hepatitis B cirrhosis, 1%

Alcoholic liver disease,

23%

B 100
90
80
% patient survival

70
60
50
Year of transplant
40
(number at risk on day 0)
30 1996–8 (1147)
20 1999–2001 (1215)
2002–4 (1239)
10 2005–8 (1451)
0
0 1 2 3 4 5 6 7 8 9 10
Years since transplant

Fig 4 (A) Indications for elective liver transplantation in the UK, January 1, 2008 –December 31, 2010. (B) Long-term patient survival after first
elective liver transplant in adults in the UK from DBD donors, January 1, 1996– December 31, 2008.

recipients must have abstained from alcohol for 6 months cardiomyopathy (Fig. 5A). Most other paediatric recipients
before listing, a period of time that may allow significant will have complex congenital heart disease and often come
recovery if there is an element of alcoholic hepatitis. Auto- to surgery after a number of previous palliative procedures.
immune disease represents most of the other indications. Problems of pre-sensitization to HLA antigens add to the
Hepatitis B, once a common indication for transplantation, substantial technical difficulties, and these patients are
now only accounts for 1% of liver transplants, reflecting very challenging. Outcomes have been improving in recent
the impact of the new anti-viral treatments for that years (Fig. 5B).
disease. It is hoped that the anti-viral drugs against hepa- Across the board, a 1 yr survival of 80 – 85% can be
titis C that are currently in development will have a similar expected, with a subsequent attrition rate of perhaps
effect on the current hepatitis C epidemic.60 Acute liver 4% annually. Late deaths are most commonly the result
failure represents about 10% of transplants performed in of graft vasculopathy. The endothelium of the graft cor-
the UK. Although such patients are prioritized for a liver onary circulation represents the zone of contact
via the national allocation scheme, one-third will die between host and recipient. Endothelial dysfunction can
before a suitable graft can be identified. be detected as early as 6 weeks post-transplant. It is
After non-urgent liver transplantation, the long-term likely that ongoing immune injury is the stimulus for sub-
outcomes are good (Fig. 4B), with a 10 yr patient survival in intimal thickening that eventually results in diffuse coron-
excess of 60%, and likely to approach 70% for the most ary arterial narrowing. Post-transplant rejection episodes,
recently transplanted patients. dyslipidaemia, and continued smoking are all predictors
of worse disease. In addition, donor age and pre-existing
Heart transplantation coronary disease are also important. Most other deaths
In both adult and paediatric practice, the most common are the consequence of prolonged immunosuppression,
indication for transplantation is idiopathic dilated with malignancy and renal failure prominent. Functional

i38
Organ transplantation BJA

A Restrictive
Other, 7% Congenital heart disease
7%
cardiomyopathy, 4%

Hypertrophic
cardiomyopathy, 8%

Other heart disease, 6%

Valvular heart disease, 2%

Dilated cardiomyopathy,
46%

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Coronary heart disease,
20%

B 100
90
80
% patient survival

70
60
50
Year of transplant
40 (number at risk on day 0)
30 1996–8 (708)
20 1999–2001 (501)
2002–4 (387)
10 2005–8 (429)
0
0 1 2 3 4 5 6 7 8 9 10
Years since transplant

Fig 5 (A) Indications for adult non-urgent heart only transplantation in the UK, January 1, 2008– December 31, 2010. (B) Long-term patient
survival after first heart only transplant in adults in the UK, January 1, 1996– December 31, 2008.

outcome is excellent, with very good quality of life lungs in the UK are currently used for transplant, and
and return to normal activities after successful while relaxation of donor criteria may permit greater ac-
transplantation. tivity, it may also result in more early graft dysfunction
Paediatric results have been improving steadily over the and patient mortality.63
past few years, perhaps reflecting the restriction of activity Although registry figures continue to suggest a 5 yr sur-
to specialist centres (just two in the UK). In particular, vival of only 50–60%, single institution results, particularly
infants presenting with cardiomyopathy may expect a 10 yr in favourable groups such as those with cystic fibrosis, can
survival approaching 90% after transplantation.61 be much better. Median survivals in excess of 10 yr have
recently been reported.64 Late attrition is largely related to
Lung transplantation progressive small-airway narrowing, termed obliterative
bronchiolitis. Although it is, in part, a chronic immune
Major indications for lung transplantation include cystic fibro-
injury, early post-implant damage is also a risk factor, and
sis, emphysema, and pulmonary fibrosis (Fig. 6A). The last
it would seem that a range of immune and non-immune
may be best treated with a single-lung transplant, but the bi-
insults set up progressive airway obliteration. The latter
lateral procedure has become the norm for most patients.
include viral infections and gastro-oesophageal reflux.
There are clear-cut advantages in terms of both early and
While in some patients, augmented immunosuppression
late survival. Very few combined heart and lung transplants
may halt the progress, for others retransplantation is the
are currently performed, and they are largely restricted to
only option.
patients with complex congenital heart disease and second-
ary pulmonary hypertension.
There remains a significant early mortality rate Summary
(Fig. 6B) which principally relates to primary graft dys- Organ transplantation is a story of remarkable achievement
function and brain-death-induced damage in the and an ongoing challenge. Immunosuppression needs to
donor.62 As a result, barely 20% of potential donor be improved to further extend the life of the grafts with

i39
BJA Watson and Dark

A Other, 13%
Alpha-1 anti-trypsin
deficiency, 8%

Primary pulmonary
hypertension, 3%

Emphysema, 28%
Fibrosing lung disease,
17%

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Bronchiectasis, 5%

Cystic fibrosis, 26%

B 100 Year of transplant

90 (number at risk on day 0)
80 1996–98 (287)
% patient survival

1999–2001 (275)
70 2002–4 (348)
60 2005–8 (455)
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10
Years since transplant

Fig 6 (A) Indications for elective lung transplantation in the UK, January 1, 2008 – December 31, 2010. (B) Long-term patient survival after first
lung transplant in adults in the UK from DBD donors, January 1, 1996 –December 31, 2008.

induction of tolerance still the goal; preservation techniques 3 Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homo-
need to be modified to reduce the ischaemic injury that transplantation of the human kidney between identical twins.
organs sustain, and which contributes to premature failure. J Am Med Assoc 1956; 160: 277– 82
Nevertheless, the main factor limiting the success of trans- 4 Woodruff MF, Robson JS, Ross JA, Nolan B, Lambie AT. Transplant-
ation of a kidney from an identical twin. Lancet 1961; 1: 1245– 9
plantation continues to be the shortage of suitable donor
5 Starzl TE, Marchioro TL, Huntley RT, et al. Experimental and clinic-
organs.
al homotransplantation of the liver. Ann N Y Acad Sci 1964; 120:
739– 65
Acknowledgements 6 Calne RY, Williams R, Dawson JL, et al. Liver transplantation in
The authors are grateful to Lisa Mumford and Rachel man. II. A report of two orthotopic liver transplants in adult reci-
pients. Br Med J 1968; 4: 541–6
Johnson and NHS Blood and Transplant for providing the
7 Dong E Jr, Lower RR, Hurley EJ, Shumway NE. Transplantation of
data for the table and Figures 1, 2A, 4A, 5A, and 6A; they
the heart. Dis Chest 1965; 48: 455–7
also provided Figures 2B, 3, 4B, 5B, and 6B.
8 Barnard CN. Human cardiac transplantation. An evaluation of the
first two operations performed at the Groote Schuur Hospital,
Declaration of interests Cape Town. Am J Cardiol 1968; 22: 584–96
None declared. 9 Ross D. Report of a heart transplant operation. Am J Cardiol 1968;
22: 838– 9
10 Caves PK, Stinson EB, Billingham ME, Shumway NE. Serial trans-
References venous biopsy of the transplanted human heart. Improved
1 Morris PJ. Transplantation—a medical miracle of the 20th management of acute rejection episodes. Lancet 1974; 1:
century. N Engl J Med 2004; 351: 2678–80 821– 6
2 Gibson T, Medawar PB. The fate of skin homografts in man. J Anat 11 Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of the
1943; 77: 299– 310.4 International Society for Heart and Lung Transplantation: twenty-

i40
Organ transplantation BJA
seventh official adult heart transplant report—2010. J Heart Lung 33 Scobie L, Takeuchi Y. Porcine endogenous retrovirus and other
Transplant 2010; 29: 1089– 103 viruses in xenotransplantation. Curr Opin Organ Transplant
12 Hardy JD, Webb WR, Dalton ML Jr, Walker GR Jr. Lung homotrans- 2009; 14: 175– 9
plantation in man. J Am Med Assoc 1963; 186: 1065– 74 34 Le Bas-Bernardet S, Blancho G. Current cellular immunological
13 Reitz BA, Wallwork JL, Hunt SA, et al. Heart–lung transplantation: hurdles in pig-to-primate xenotransplantation. Transplant
successful therapy for patients with pulmonary vascular disease. Immunol 2009; 21: 60–4
N Engl J Med 1982; 306: 557–64 35 Ross H, Marshall VC, Escott ML. 72-hr canine kidney
14 Patterson GA. Bilateral lung transplant: indications and tech- preservation without continuous perfusion. Transplantation
nique. Semin Thorac Cardiovasc Surg 1992; 4: 95–100 1976; 21: 498– 501
15 Mathé G, Thomas EG, Ferrebee JW. The restoration of marrow 36 Southard JH, Belzer FO. The University of Wisconsin organ preser-
function after lethal irradiation in man: a review. Transplant Bull vation solution: components, comparisons, and modifications.
1959; 6: 407 Transplant Rev 1993; 7: 176– 90
16 Hamburger J, Vaysse J, Crosnier J, Auvert J, Lalanne CL, Hopper J. 37 Faenza A, Catena F, Nardo B, et al. Kidney preservation with uni-
Transplantation of a kidney between nonmonozygotic twins after versity of Wisconsin and Celsior solution: a prospective multicen-
irradiation of the receiver. Good function at the fourth month. ter randomized study. Transplantation 2001; 72: 1274–7

Downloaded from http://bja.oxfordjournals.org/ at Australian & NZ College of Anaesthetists on July 27, 2013
Presse Med 1959; 67: 1771– 5 38 Banner NR, Thomas HL, Curnow E, Hussey JC, Rogers CA,
17 Merrill JP, Murray JE, Harrison JH, Friedman EA, Dealy JB, Bonser RS. The importance of cold and warm cardiac ischemia
Dammin GJ. Successful homotransplantation of the kidney for survival after heart transplantation. Transplantation 2008;
between nonidentical twins. N Engl J Med 1960; 262: 86: 542–7
1251– 60 39 Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics
18 Calne RY. Inhibition of the rejection of renal homografts in dogs associated with liver graft failure: the concept of a donor risk
by purine analogues. Transplant Bull 1961; 28: 65– 81 index. Am J Transplant 2006; 6: 783– 90
19 Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of 40 Rao PS, Schaubel DE, Guidinger MK, et al. A comprehensive risk
cyclosporin A: a new antilymphocytic agent. Agents Actions quantification score for deceased donor kidneys: the kidney
1976; 6: 468– 75 donor risk index. Transplantation 2009; 88: 231–6
20 Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients receiv- 41 Axelrod DA, Sung RS, Meyer KH, Wolfe RA, Kaufman DB. Sys-
ing renal allografts from cadaver donors. Lancet 1978; 2: tematic evaluation of pancreas allograft quality, outcomes
1323– 7 and geographic variation in utilization. Am J Transplant 2010;
21 Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated 10: 837– 45
with sirolimus therapy in renal-transplant recipients. [see 42 Simpson P. A Code of Practice for the Diagnosis and Confirmation
comment]. N Engl J Med 2000; 343: 225–6 of Death. London: Academy of Medical Royal Colleges, 2008
22 Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention 43 Merion RM, Pelletier SJ, Goodrich N, Englesbe MJ, Delmonico FL.
of allograft rejection and vasculopathy in cardiac-transplant reci- Donation after cardiac death as a strategy to increase deceased
pients [see comment]. N Engl J Med 2003; 349: 847– 58 donor liver availability. Ann Surg 2006; 244: 555– 62
23 Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to 44 Dark JH. Lung transplantation from the non-heart beating donor.
sirolimus: a successful treatment for posttransplantation Transplantation 2008; 86: 200–1
Kaposi’s sarcoma. Transplantation 2004; 77: 760– 2 45 Valero R, Cabrer C, Oppenheimer F, et al. Normothermic
24 Figlin RA. Mechanisms of disease: survival benefit of temsirolimus recirculation reduces primary graft dysfunction of kidneys
validates a role for mTOR in the management of advanced RCC. obtained from non-heart-beating donors. Transpl Int 2000; 13:
Nat Clin Pract Oncol 2008; 5: 601–9 303– 10
25 Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to 46 Fondevila C, Hessheimer AJ, Ruiz A, et al. Liver transplant using
calcineurin inhibitors in renal transplantation. N Engl J Med 2007; donors after unexpected cardiac death: novel preservation
357: 2562– 75 protocol and acceptance criteria. Am J Transplant 2007; 7:
26 Collett D, Mumford L, Banner NR, Neuberger J, Watson CJE. Com- 1849– 55
parison of the incidence of malignancy in recipients of different 47 Pelletier S, Hundley J, Englesbe M, Rojas A, Bartlett R, Punch J.
types of organ: a UK registry audit. Am J Transplant 2010; 10: Liver transplantation and ECMO-assisted donation after cardiac
1889– 1896 death. Am J Transplant 2009; 9: 263
27 Orlando G, Soker S, Wood K. Operational tolerance after liver 48 Watson CJ, Wells AC, Roberts RJ, et al. Cold machine perfusion
transplantation. J Hepatol 2009; 50: 1247–57 versus static cold storage of kidneys donated after cardiac
28 Calne RY. Prope tolerance with alemtuzumab. Liver Transpl 2005; death: a UK multicenter randomized controlled trial. Am J Trans-
11: 361–3 plant 2010; 10: 1991–9
29 Ohe H, Li Y, Nafady-Hego H, et al. Minimal but essential doses of 49 Jochmans I, Moers C, Smits JM, et al. Machine perfusion versus
immunosuppression: a more realistic approach to improve long- cold storage for the preservation of kidneys donated after
term outcomes for pediatric living-donor liver transplantation. cardiac death: a multicenter, randomized, controlled trial. Ann
Transplantation 2011; 91: 808–10 Surg 2010; 252: 756–64
30 NHS Blood and Transplant. Transplant activity in the U.K. Activity 50 Nocito A, El-Badry AM, Clavien P-A. When is steatosis too much
Report 2009/10. Bristol, 2010 for transplantation? J Hepatol 2006; 45: 494– 9
31 Manara AR, Murphy PG, O’Callaghan G. Donation after circulatory 51 Vogel T, Brockmann JG, Friend PJ. Ex-vivo normothermic liver per-
death. Br J Anaesth 2012; 108 (Suppl. 1): i108–i121 fusion: an update. Curr Opin Organ Transplant 2010; 15: 167–72
32 Schmelzle M, Schulte Esch J II, Robson SC. Coagulation, platelet 52 Brockmann J, Reddy S, Coussios C, et al. Normothermic
activation and thrombosis in xenotransplantation. Curr Opin perfusion: a new paradigm for organ preservation. Ann Surg
Organ Transplant 2010; 15: 212–8 2009; 250: 1–6

i41
BJA Watson and Dark

53 Harper S, Hosgood S, Kay M, Nicholson M. Leucocyte depletion 59 Byrne C, Steenkamp R, Casteldine C, Ansell D, Feehally J. UK ESRD
improves renal function during reperfusion using an experimen- Prevalent rates in 2008: national and centre specifc analysis. UK
tal isolated haemoperfused organ preservation system. Br J Renal Registry 12th Annual Report. Bristol: The Renal Association,
Surg 2006; 93: 623–9 2010; 41– 67
54 Steen S, Sjoberg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Trans- 60 Fowell AJ, Nash KL. Telaprevir: a new hope in the treatment of
plantation of lungs from a non-heart-beating donor. Lancet chronic hepatitis C? Adv Ther 2010; 27: 512–22
2001; 357: 825–9 61 Kirk R, Edwards LB, Kucheryavaya AY, et al. The registry of the
55 Lindstedt S, Hlebowicz J, Koul B, et al. Comparative outcome of international society for heart and lung transplantation: thir-
double lung transplantation using conventional donor lungs teenth official pediatric heart transplantation report—2010.
and non-acceptable donor lungs reconditioned ex vivo. Interact J Heart Lung Transplant 2010; 29: 1119–28
Cardiovasc Thorac Surg 2011; 12: 162– 5 62 Avlonitis VS, Fisher AJ, Kirby JA, et al. Pulmonary transplantation:
56 Steen S, Ingemansson R, Eriksson L, et al. First human transplant- the role of brain death in donor lung injury. Transplantation 2003;
ation of a nonacceptable donor lung after reconditioning ex vivo. 75: 1928–33
Ann Thorac Surg 2007; 83: 2191– 4 63 Botha P, Fisher AJ, Dark JH. Marginal lung donors: a
57 Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion diminishing margin of safety? Transplantation 2006; 82:
in clinical lung transplantation. N Engl J Med 2011; 364: 1431– 40 1273– 9

Downloaded from http://bja.oxfordjournals.org/ at Australian & NZ College of Anaesthetists on July 27, 2013
58 Gurusamy KS, Kumar Y, Sharma D, Davidson BR. Ischaemic 64 Meachery G, De Soyza A, Nicholson A, et al. Outcomes of lung
preconditioning for liver transplantation. Cochrane Database transplantation for cystic fibrosis in a large UK cohort. Thorax
Syst Rev 2008, issue 1, article No CD006315 2008; 63: 725– 31

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